The damaging effects of sunlight on skin are well documented. Much damage is due to routine day-to-day activities in the sunlight.
The major short term hazard of prolonged exposure to sunlight is erythema (i.e., sunburn). The 290 to 320 nanometer wavelength ultraviolet radiation range, designated as the "UVB" wavelength range, tends to be the primary cause of erythema. The 320 to 400 nanometer wavelength ultraviolet radiation range, designated as the "UVA" wavelength range, also produces erythema.
In addition to the short term hazard of erythema, there are also long term hazards associated with UV radiation exposure. One of these long term hazards is malignant changes in the skin surface. Numerous epidemiologic studies demonstrate a strong relationship between sunlight exposure and human skin cancer. Another long term hazard of ultraviolet radiation is premature aging of the skin. This condition is characterized by wrinkling and yellowing of the skin, along with other physical changes such as cracking, telangiectasis (spider vessels), solar keratoses (growths), ecchymoses (subcutaneous hemorrhagic lesions), and loss of elasticity (sagging). The adverse effects associated with exposure to UVA and UVB wavelength radiation are more fully discussed in DeSimone, "Sunscreen and Suntan Products", Handbook of Nonprescription Drugs, 7th Ed, Chapter 26, pp. 499-511 (American Pharmaceutical Association, Washington, D.C.; 1982); Grove and Forbes, "A Method for Evaluating the Photoprotection Action of Sunscreen Agents Against UV-A Radiation", International Journal of Cosmetic Science, 4, pp. 15-24 (1982); and U.S. Pat. No. 4,387,089, DePolo, issued Jun. 7, 1983. Hence, although the immediate effects of ultraviolet radiation may be cosmetically and socially gratifying, the long-term hazards are cumulative and potentially serious.
Sunblock agents are commercially available to protect the skin from UV radiation. These agents scatter or reflect ultraviolet radiation. Examples include titanium dioxide and zinc oxide. However, these agents are very susceptible to rub-off or wear-off resulting in little or no protection.
The most common agents for sun protection are sunscreens. These agents exert their effects through absorption of ultraviolet radiation so that it cannot penetrate the skin. Sunscreens must remain on the surface of the skin during exposure. However, sunscreens are easily rubbed off or washed off by sweating or swimming and can also be lost by penetration into the skin.
Conjugated dienoic acids and their derivatives, in general, are known to be useful as quenchers for protecting the skin from harmful effects of UV exposure. For example, the use of a number of compounds, including 2,4-hexadien-1-ol, for controlling the chronic effects of prolonged exposure to sunlight is disclosed in U.S. Pat. No. 4,098,881, Majeti, issued Jul. 4, 1978. The use of sorbic acid or salts thereof in sunscreen formulations is also known. See e.g., U.S. Pat. No. 4,264,581, Kerkhof et al., issued Apr. 28, 1981.
Tocopherol (Vitamin E) and its esters have been disclosed for use as a photoprotector in topical compositions, without interfering with the tanning response. See, e.g., U.S. Pat. No. 4,144,325, Voyt, issued Mar. 13, 1974; U.S. Pat. No. 4,248,861, Schutt, issued Feb. 3, 1981; U.S. Pat. No. 4,000,276, Hasunuma et al., issued Dec. 28, 1976; U.S. Pat. No. 4,847,071, Bissett, Bush, and Chatterjee, issued Jul. 11, 1989; and European Patent Application 166,221, Tuominen, published Jan. 2, 1986.
Hart, Cosmetics and Toiletries, 93(12), 28-30 (1978), discloses the utilization of low levels of chelating agents such as ethylenediaminetetraacetic acid (EDTA) in cosmetic formulations as preservatives. Particularly disclosed is the use of EDTA in sunscreen lotions and creams to prevent dark color formation from the reaction of p-aminobenzoic acid derivatives with iron. See also, Hart, Cosmetics and Toiletries, 98(4), 54-58 (1983). Japanese Patent Application 61-215,314 discloses a topical composition for protecting skin from UV-rays containing EDTA or a phosphoric acid or salt, 4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane and inorganic powders. The acids and their salts are added as preservatives. See also Japanese Patent Application 61-215,313, published Sep. 25, 1986, and U.S. Pat. No. 4,579,844, Rovee, issued Apr. 1, 1986. Wooley, et al., Biochem. J., 169, 265-276 (1978), discloses the inhibition of skin collagenase utilizing EDTA, 1,10-phenanthroline, cysteine, dithiothreitol, or sodium aurothiemaleate.
It is well-known that ultraviolet light induces inflammation of the skin and harmful photochemical reactions therein. During exposure and as repair of the UV damage takes place, super-oxide (O.sub.2.sup.-) radicals are formed in the skin. UV irradiation also causes some microvascular damage in the skin. (See Kligman et al., Photoderm., 3, 215-227 (1986)). This leads to local hemorrhage and "leakage" of blood cells into the dermis. Iron from the hemoglobin accumulates in the extra-cellular matrix of the tissue as Fe.sup.+2 and Fe.sup.+3. It is known that iron catalytically participates in the conversion of superoxide radicals to hydroxyl radicals, a species which is known to be very damaging to tissue. (See Davies, J. Biol. Chem., Vol. 262, No 20 (1987), pp. 9895-9901.) Another process which is damaging to tissue is membrane lipid peroxidation, which is also accelerated by iron. (See Halliwell and Gutteridge, Free Radicals in Biology and Medicine, Claredon Press, Oxford, England (1985), p. 147.)
In addition to their role in UV radiation induced tissue damage, oxygen radicals are known to be capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acids, proteins and free amino acids, lipids and lipoproteins, carbohydrates, and connective tissue macromolecules. These compounds may have an impact on such cell activities as membrane function, metabolism, and gene expression. (See C. E. Cross, G. Halliwell, E. T. Borish, W. A. Pryor, B. N. Ames, R. L. Saul, J. M. McCord, and D. Harman, "Oxygen Radicals and Human Disease", Annals of Internal Medicine 107(4), 526-545 (1987).) Clinical conditions in which oxygen radicals are thought to be involved include those concerning multiorgan involvement, including inflammatory-immune injury such as glomerulonephritis (idiopathic, membranous), vasculitis (hepatitis B virus, drugs), autoimmune disease; ischemia-reflow states; drug and toxin-induced reactions; iron overload such as idiopathic hemochromatosis, dietary iron overload (red wine, beer brewed in iron pots), thalassemia and other chronic anemias; nutritional deficiencies, such as Kwashiorkor, vitamin E deficiency; alcohol; radiation injury; aging, such as disorders of "premature aging", immune deficiency of age; cancer and amyloid diseases. Additional conditions in which oxygen radicals are thought to be involved include those concerning primary single organ involvement including erythrocyte related conditions, such as phenylhydrazine, primaquine, lead poisoning, protoporphyrin photo-oxidation, malaria, sickle-cell anemia, favism, Fanconi anemia; lung related conditions such as cigarette-smoking effects, emphysema, hyperoxia, bronchopulmonary dysplasia, oxidant pollutants, acute respiratory distress syndrome, mineral dust pneumoconiosis, bleomycin toxicity, paraquat toxicity; heart and cardiovascular system related conditions, such as alcohol cardiomyopathy, Keshan disease (selenium deficiency), atherosclerosis, doxorubicin toxicity; kidney related conditions, such as nephrotic antiglomerular basement membrane disease, aminoglycoside nephrotoxicity, heavy metal nephrotoxicity, renal graft rejection; gastrointestinal tract related conditions, such as endotoxin liver injury, carbon tetrachloride liver injury, diabetogenic action of alloxan, free-fatty-acid-induced pancreatitis, nonsteroidal-anti-inflammatory-drug induced lesions; joint abnormalities, such as rheumatoid arthritis; brain related conditions, such as hyperbaric oxygen, neurotoxins, senile dementia, Parkinson disease-MPTP, hypertensive cerebrovascular injury, cerebral trauma, neuronal ceroid lipofuscinoses, allergic encephalomyelitis and other demyelinating diseases, ataxia-telangiectasia syndrome, potentiation of traumatic injury, aluminum overload, a-beta-lipoproteinemia; eye related conditions, such as cataractogenesis, ocular hemorrhage, degenerative retinal damage, retinopathy of prematurity, photic retinopathy and skin related conditions, such as solar radiation, thermal injury, porphyria, contact dermatitis, photosensitive dyes, and bloom syndrome. (See Cross, et. al., 1987.)
Black, Photochem. Photobiol., 46(2), 213-221 (1987), speculates, based on circumstantial evidence, that free radicals may cause at least some UV-induced skin damage. The effect of systemically or intraperitoneally administered anti-oxidants on peroxide formation is discussed.
Braughler, et al., J. Biol. Chem., 261(22), 10282-10289 (1986), discusses iron-initiated lipid peroxidation reactions in the context of brain synoptosomes. It is shown that the use of a chelator, EDTA, will prevent the reactions from starting.
Nunez et al., J. Biol. Chem., 258(2), 1146-1151 (1983), discusses the cellular mechanism by which iron is released by reticulocytes. It was found that iron (II) chelators (e.g., phenanthroline, dipyridyl), but not iron (III) chelators, were useful in the study of this mechanism.
deMello Filho, et al., Biochem. et Biophys. Acta, 847, 82-89 (1985), describes cell culture work which suggests that the inhibition of the iron-initiated peroxidation reaction by phenanthroline may prevent cellular damage caused by inflammation.
Morgan, Biochem. Biophys. Acta, 733(1), 39-50 (1983), discusses the mechanism by which certain iron chelators inhibit cellular iron uptake after release from transfertin while it is still in the membrane fraction of the cells.
European Patent Application 0 313 305, Bissett, Bush, and Chatterjee, published Apr. 26, 1989, discloses photoprotection compositions comprising various chelating agents, including 2-furildioxime.
It is an object of the present invention to provide a pharmaceutical composition, the use of which will regulate biochemical damage resulting from free radical reactions in living persons.
It is also an object of the present invention to provide a method for regulating biochemical damage resulting from free radical reactions in living persons.
It is also an object of the present invention to provide a topical composition in a stable form, the use of which will prevent chronic (photoaging) effects of exposure to the sun.
It is also an object of the present invention to provide a topical composition for preventing the deleterious effects of the sun with minimal interference to the tanning response.
It is also an object of the present invention to provide a cleansing composition for preventing the deleterious effects of the sun with minimal interference to the tanning response.
It is also an object of the present invention to provide a method for preventing the deleterious effects of the sun with minimal interference to the tanning response.
It is further an object of the present invention to provide a photoprotection composition which penetrates into the skin and which has low susceptiblility to rub-off, wear-off or wash-off.
It is a still further object of the present invention to provide a photoprotection composition which can be applied to the skin in advance of UV exposure without significant loss of efficacy.